Report from the American Academy of Neurology annual meeting, Boston MA, 22-28 April  2017

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CONGRESS HIGHLIGHTS – THURSDAY EDITION
Ocrelizumab
Teriflunomide
Dimethyl fumarate
Fingolimod
Alemtuzumab
Natalizumab
Cladribine

Ocrelizumab: A post-hoc analysis of data from the newly-published OPERA trials I and II (Hauser et al. N Engl J Med 2017;376:221-34) reported that ocrelizumab reduced the cumulative probability of relapse vs. interferon-beta-1a by week 8 of treatment; the annualized relapse rate (ARR) from baseline to week 8 was also significantly lower (0.12 vs. 0.27) (Hauser et al. AAN 2017; abstract S31.002).

The proportion of patients with no evidence of disease activity (NEDA) at 96 weeks in the phase III trials was 47.9% with ocrelizumab vs. 29.2% with interferon-beta-1a, and 47.5% and 25.1%, respectively. A new analysis showed similar NEDA results in the subgroup with early MS (mean age 34 years; mean time from diagnosis 6 months): 47.6% with ocrelizumab vs. 28.0% with IFN-beta-1a (pooled results) (Havrdova et al. AAN 2017; abstract P4.391). A similar analysis – no evidence of progression or active disease, or NEPAD – was performed on the ORATORIO dataset in PPMS (Montalban et al. N Engl J Med 2017;376:209-20). NEPAD is a new composite measure comprising no 12-week confirmed disability progression, no 12-week confirmed worsening >20% on the Timed 25-Foot Walk and 9-Hole Peg Test, no Gd+ T1 lesions and no new/enlarging T2 lesions. NEPAD rates at week 120 were 29.9% with ocrelizumab vs. 9.4% with placebo (Wolinsky et al. AAN 2017; abstract P4.384).

Preliminary results are also available from the first 48 weeks of the open-label extension of OPERA I/II (Naismith et al. AAN 2017; abstract S31.004). Active controls were switched from IFN-beta and received a median of two doses of ocrelizumab. ARR declined from 0.245-0.254 during IFN-beta to 0.092-0.115 with ocrelizumab. ARR in the continuous ocrelizumab group was 0.100-0.118.

Safety results have been updated based on data from phase II and III trials (5711 patient-years of exposure) (Kappos et al. AAN 2017; abstract P5.407). The rate of serious adverse events was 6.97 per 100 patient-years; and 1.80/100 PY for serious infections. The incidence of malignancies, originally reported to be 0.40/100 PY (Hauser 2017), is now 0.44/100 PY.

Teriflunomide: Brain volume changes were determined using data from the TEMSO trial of teriflunomide (Freedman et al. AAN 2017; abstract P6.362). In treatment-naïve subjects, the median percentage change in brain volume was reduced 30% from baseline in year 1, and 17% in year 2 compared to the two years prior to entry. Baseline brain volume was lower in the previously-treated group; the rate of brain volume loss was reduced 53% and 51% in years 1 and 2 of treatment. A separate analysis of TOPIC data in CIS/early MS reported a significant reduction in the rate of change in cortical grey-matter volume in Years 1 (61% difference) and 2 (40% difference) vs. placebo (Zivadinov et al. AAN 2017; abstract P6.334).

Dimethyl fumarate: The impact of sequencing from natalizumab to DMF on lymphocyte counts was examined in a post-hoc analysis from the REALIZE observational study (Buckle et al. AAN 2017; abstract P5.376). In prior natalizumab-treated subjects, baseline ALC was higher, and there were greater decreases in ALC following DMF initiation. The ALC decrease from baseline was 56.4% with prior NTZ vs. 34.4% with no prior NTZ at 12 months. Comparable declines in CD4+ and CD8+ counts were also observed.

Fingolimod: MS and Clinical Outcome and MRI in the US (MS-MRIUS) is a retrospective study of about 600 RRMS patients treated with fingolimod. The NEDA rate following fingolimod initiation was 60.5%; and 38.1% achieved NEDA-4 (NEDA + no brain volume loss >0.4%) (Weinstock-Guttman et al. AAN 2017; abstract P4.388). The median annualized brain volume loss declined from 0.34% to 0.30% with fingolimod, and 94.5% of fingolimod-treated patients had no Gd+ lesions (Zivadinov et al. AAN 2017; abstract P5.350).

Alemtuzumab: An analysis was performed on the subgroup of patients with ongoing disease activity following one course of treatment with alemtuzumab in the CARE-MS II trial (Singer et al. AAN 2017; abstract P5.349). Overall, 14% of patients relapsed 6-12 months after the first course. ARR declined to 0.6 after the second course of treatment, and declined further to 0.4 in Year 3, 0.3 in Years 4-5, and 0.1 in Year 6, results that were comparable to the overall CARE-MS II population. The proportion with no 6-month confirmed disability worsening was 61% through Year 6.

Natalizumab: It has been suggested that DMTs may take several years to stabilize disease progression in patients with significant disability (Sormani et al. ECTRIMS 2016; abstract 215). This concept is supported by a new analysis of the ASCEND trial of natalizumab (Hartung et al. AAN 2017; abstract P5.330; and Giovannoni et al. Abstract P5.359). During the 2-year study period, treatment did not delay disability progression, as evaluated by a composite endpoint (EDSS, T25FW, 9HPT) (Steiner et al. AAN 2016; abstract P009). During the long-term extension, there was a lower risk of progression in patients on continuous natalizumab vs. placebo-natalizumab switchers (52% vs. 61%). The greatest benefit was seen on upper-limb function.

Cladribine: Oral cladribine is currently in development and is expected to become available in the next year. Dosing is 3.5 mg/kg cumulative administered over 10 treatment days in a 2-year period. A new safety analysis examined data from phase III studies in RRMS (CLARITY) and CIS/early MS (ORACLE-MS) (Cook et al. Mult Scler 2011;17:578-593. Leist et al. Lancet Neurol 2014;13:257-267). Total exposure to cladribine 3.5 mg/kg was 3432.65 patient-years (Cook et al. AAN 2017; abstract P5.394). The incidence of serious adverse events was 4.0 per 100 patient-years vs. 3.6/100 PY with placebo. The incidence of herpes zoster was 0.83/100 PY with cladribine vs. 0.20/100 PY with placebo; for neoplasms it was 1.14 and 1.01, respectively.

A separate analysis of lymphocyte recovery in the CLARITY + extension reported that the absolute lymphocyte count (ALC) reached a nadir at 9 weeks after the first treatment course, and at 7 weeks after the second treatment course (Soelberg-Sorensen et al. AAN 2017; abstract P5.379). ALC gradually returned toward baseline after each course, and was within normal range in all patients beyond year 2.

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CONGRESS HIGHLIGHTS – WEDNESDAY EDITION
Dementia
Parkinson’s disease
Epilepsy
Multiple sclerosis

Dementia
Rapidly progressive dementia: RPD is often attributed to prion diseases such as Creutzfeldt-Jacob disease, but this emphasis overlooks more common causes, according to a 10-year retrospective analysis of 67 RPD cases (Day et al. AAN 2017; abstract P5.083). Over 90% of RPD cases could be attributed to neurodegenerative dementing illnesses; the most common cause was Alzheimer’s disease. Older age at onset increased the probability of an AD diagnosis. Cortical visual signs and parkinsonism were predictive of other dementias. Contributing factors to RPD were cerebrovascular disease and mood disorders.

A separate retrospective analysis of younger RPD patients (mean age 49 years; n=187) treated at a tertiary care hospital found that dementia was reversible in a majority of cases (Patil et al. AAN 2017; abstract P5.085). Causes of reversible dementia (58% of cases) were immune-mediated encephalitis; neoplastic disorders; infections; CNS vasculitis; nutritional and metabolic disorders; demyelinating disorders; and pseudodementia. Causes of irreversible dementia included primary neurodegenerative conditions and vascular cognitive impairment. Prion diseases were the underlying cause in 7% of RPD cases. Neoplastic disorders presented early (less than 6 months); whereas neurodegenerative dementias presented later (>6 months).

Parkinson’s disease
Dementia in PD: A population-based cohort study in the U.S. reported that 42% of PD patients developed PD-associated dementia during the 15-year incidence period (Ali et al. AAN 2017; abstract P5.007). The sample comprised 176 males (59%) and 122 females; mean age at PD diagnosis was 74 years. Mean age at onset of cognitive dysfunction was 79 years. In the subgroup with cognitive impairment, the mortality rate was 68% at the most recent follow-up. The mean time from onset of cognitive impairment to death was 4.5 years.

Epilepsy
Triggers: Seizure triggers were investigated in a national sample of epilepsy patients using the EpiWatch app available on the Apple Watch and iPhone (Ge et al. AAN 2017; abstract S37.002). A total of 177 participants reported seizure triggers. The most common triggers were stress (37%), missing sleep (18%), menstruation (12%), overexertion (11%), diet (9%), missed medications (7%), and fever/infection (6%). Stress was a more common trigger in subjects working full-time vs. working part-time or unemployed (35.0% vs. 20.8% and 27.3%). Among younger subjects, 39.5% reported that treatment non-adherence was a seizure trigger.

Multiple sclerosis
Oligoclonal bands: The Stockholm MS Center examined the significance of OCB positivity and number on radiological outcomes in a long-term follow-up of 40 MS patients (Evertsson et al. AAN 2017; abstract P4.397). OCB+ subjects had a mean of 10.6 bands (range 2-20). The follow-up period ranged from 0.5 to 14 years. A higher number of OCBs was a significant predictor of brain atrophy over the long term, but not over the short term. Baseline OCB number was the only significant predictor of brain atrophy. A prior study reported that a higher OCB number was prognostic of poorer outcomes (Avasarala et al. Arch Neurol 2001;58:2044-2045).

Salt: Higher salt consumption has been linked to increased clinical and radiological disease activity in MS patients (Farez et al. ECTRIMS 2014; abstract P351). However, two studies presented at last year’s AAN found no association between salt intake and MS (Cortese et al. AAN 2016, abstract S37.001; Fitzgerald et al., abstract S37.002). An EAE study now reports that a high-salt diet has effects on the gut microbiome, notably by depleting Lactobacilli (Linker et al. AAN 2017; abstract P3.391). A high-salt diet was associated with a higher frequency of pathogenic Th17 cells; this could be prevented by concomitant treatment with L. murinus supplementation.

Vitamin A: Retinoic acid enhances immune tolerance and regulates T and B cell populations, prompting the suggestion that vitamin A supplementation may be beneficial in MS management (Dorosty-Motlagh et al. J Mol Neurosci 2016;60:82-90). A new study examined the relationship between vitamin A levels, EDSS score and T2 lesion volume in 26 RRMS patients with normal vitamin D levels (Puttagunta et al. AAN 2017; abstract P3.393). There was no significant difference in vitamin A levels in subjects with an EDSS score less than 5 vs. greater than 5. Higher vitamin A levels were associated with a lower T2 lesion volume; differences did not achieve significance, but the authors noted that there may be a long-term protective effect. A 1-year study of vitamin A in RRMS reported that supplementation had no effect on annualized relapse rates or EDSS change, but there was significant improvement in MSFC scores (Bitarafan et al. Arch Iran Med 2015;18:435-440). No significant difference was observed in T2 lesion volume with vs. without vitamin A supplementation in that study.

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CONGRESS HIGHLIGHTS – TUESDAY EDITION
Multiple sclerosis
Alzheimer’s disease
Parkinson’s disease
Stroke

Multiple sclerosis
Pregnancy: A U.S. survey of 101 neurologists found that 95% prescribe DMTs in women of childbearing age, 55% in women actively trying to get pregnant, 36% during pregnancy, and 40% during breastfeeding (Travis et al. AAN 2017; P1.358). The most commonly prescribed DMT during pregnancy/breastfeeding was glatiramer acetate.

A review of phase III trial data reported that pregnancy rates on trial ranged from 0-2% (Shirani et al. AAN 2017; abstract P1.363). The highest unintended pregnancy rate (2.2%) was recorded in the DEFINE and CONFIRM trials of dimethyl fumarate.

Passing the sniff test: Two studies have reported that olfactory changes may be a useful marker of neurodegeneration and may predict relapse activity. (Bsteh et al. AAN 2017; abstract P2.360). A prospective two-year observational study evaluated olfactory changes in 103 RRMS patients; the method used was Sniffin’ Sticks, which test subjects’ ability to identify 12 odours. Odour identification at baseline was significantly correlated with EDSS score, retinal nerve fibre layer thickness (assessed with optical coherence tomography), and cognition (assessed with Single Digit Modalities testing) at baseline, month 12 and month 24. Odour identification was generally stable over time. However, worsening olfaction was associated with an increased risk of EDSS progression (hazard ratio 2.4) and SDMT worsening (HR 2.9) at month 24. In a second analysis of the same cohort, worsening olfaction was correlated with relapse number over the next 12 months but not with the relapse number over the next 24 months (Bsteh et al. AAN 2017; abstract P2.347). Olfactory thresholds were better in patients receiving higher-efficacy agents (natalizumab, fingolimod), but not in those on lower-efficacy agents (interferon-beta, glatiramer acetate, dimethyl fumarate).

Lipid biomarkers: A comparison of blood samples from 27 RRMS patients and 9 matched controls reported significant differences in very-low density and high-density lipoprotein (VLDL, HDL) (Mckechnie et al. AAN 2017; abstract P2.345). Three sub-fractions (VLDL-2-free cholesterol, VLDL-1 cholesterol and total triglycerides) were correlated with EDSS score independently of age or sex, and could discriminate RRMS from healthy controls with high specificity (1.0) and sensitivity (0.75).

DMT discontinuation: Most older patients with RRMS who discontinue their DMT have low rates of clinical or radiological disease activity (Hua et al. AAN 2017; abstract P2.401). The sample included 724 patients older than age 60 years who had been on a DMT for at least 2 years; 211 subjects (mean age 68.6 years; mean disease duration 21 years, mean DMT duration 12.5 years) stopped treatment during the observation period. Reasons for discontinuation were treatment-related adverse effects (48%), clinical stability (29%), age (23%), and secondary progression (20%). A total of 9.5% re-started a DMT due to patient or physician preference, MRI changes and/or clinical progression.

Brain atrophy: An analysis of serial brain MRIs obtained over a 5-year period in subjects with clinically isolated syndrome or relapse-onset MS reported that putamen volume change was the best predictor of clinical outcomes (Azevedo et al. AAN 2017; abstract S16.004). Each 1%/year loss in putamen volume was associated with EDSS worsening of 0.13 points. Putamen volume loss was also correlated with sustained worsening in PASAT scores. Changes in subcortical grey matter, caudate, thalamus and cuneus were also useful measures. The estimated sample size needed in a trial setting to detect a significant neuroprotective effect was 50-80 subjects per arm. The analysis used 3T scanners, 1 mm3 3D T1 images, processed with FreeSurfer (v5.3) software.

Alzheimer’s disease
BMI: An analysis of AD neuropathology in a sample of autopsies from the U.S. National Alzheimer’s Coordinating Center database (n=1,421) found that lower body-mass index in late-life was predictive of Alzheimer’s neuropathology and clinical dementia (Duskin et al. AAN 2017; abstract P2.093). The analysis controlled for age, education, race, sex and APOEe4. Late-life BMI was not associated with cerebrovascular disease and was not predictive of Ischemic Injury Scale score.

Mucosal p-tau: The proportion of p-tau-positive cells in oral mucosal cells is significantly higher in patients with Alzheimer’s disease compared to healthy age-matched controls (Arredondo et al. AAN 2017; abstract P01.097). Positive cells were identified using image analysis from immunohistochemistry, and by flow cytometry. There were also higher levels of p-tau mRNA in AD subjects, as determined by real-time quantitative PCR. The results suggest that oral mucosal swabs may be used to support an AD diagnosis.

Parkinson’s disease
Heart rate variability (HRV): HRV due to autonomic denervation early in the clinical course of Parkinson’s disease has been proposed as an early biomarker to screen for PD prior to the onset of motor symptoms. A concern, however, is that HRV becomes less common with age. A new study assessed HRV in 164 older PD subjects and healthy controls (Christiansen et al. AAN 2017; abstract P01.110). Mean age was 75 years for PD patients and 81 years for controls. None of the HRV or EKG variables assessed differentiated PD subjects and controls, suggesting that HRV may be a useful measure only in younger subjects.

Stroke
Post-stroke seizures: An analysis of the U.S. Nationwide Readmissions database found that the incidence of seizure in the one year post-stroke was low (Chaudhry et al. AAN 2017; abstract P2.245). The large dataset (n-557,033) included patients with ischemic stroke (IS; 89.3% of the sample), intracerebral hemorrhage (ICH; 7.8%); and subarachnoid hemorrhage (SAH; 2.9%). The estimated 1-year seizure rate was 1.01%. Predictors of seizure included seizure during hospitalization (odds ratio 7.51), sodium abnormalities during hospitalization (OR 1.43), age 60 years or younger (OR 1.26), and female sex (OR 1.14), The analysis did not support the use of routine anti-epileptic drug prophylaxis post-stroke.

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